Microfluidic nasal epithelial ALI model to evaluate inhalationtoxicity caused by engineered nanomaterials

Project Summary AbstractThe twenty first century has seen a global rise in human health problems caused by air pollutionand urban exposure to aerosolized particulate matterPMhas been strongly linked to respiratory diseaseSignificant pulmonary health risks are associated with ultrafine PMPMandltm or PMwhose levels exceed global urban air quality standards for the majority of the world s population and can lead to premature mortalityWith the rapid growth of the nanotechnology sectorthe release of engineered nanomaterialsENMsnminto the environmentdeposition in the respiratory tract and the potential for toxicity are matters of growing concernThe nasal cavity serves as one of the first physical barriers to inhaled ENMswhere aerosolized nanoparticles can lodge in the nasal epithelial layer and induce toxicity responsesAlthough in vivo models have provided valuable toxicological data using defined mixtures of nanoparticlesresponses in animal models do not always correlate to human toxicity responsesHencethere is a growing need to developvalidateand utilize new in vitro alternatives that physiologically reproduce the nasal microenvironment and provide more economicalethicaland effective nanotoxicology platformsWe propose to develop an in vitro assay for toxicological analysis of nasal epithelia after aerosolized ENM exposureDuring Phase Iwe will demonstrate and test a vascularized airway microfluidic platform that incorporates primarydifferentiatednasal epithelial cells grown in an air liquid interfaceALIFollowing multiscale computational modeling of nanoparticle distribution dynamics in the human nasal cavitywe will evaluate the distribution and toxicity of selected aerosolized ENMs using the nasal ALI microfluidic modelDifferential gene expression analysis of specific toxicology pathways will be performedand the in vitro analysis will be validated against available in vivo dataGene expression data will be integrated into our high fidelity computational platform to demonstrate a systems based analysis of ENM inhalationdistribution and toxicologyIn Phase IIwe will expand the platform through device multiplexing and linking the nasal and previouslydeveloped lung ALI models together to form a combined respiratory inhalation model for nanotoxicology screeningThe developed in vitro microphysiological platform with multiple endpoint analysis will provide a robust and cost saving model for evaluating nanoparticle distributionaggregation and respiratory toxicity responses in humans Project NarrativeUltrafine particulate air pollutants such as engineered nanomaterialsENMspose significant shortand longterm exposure risks to the human airwaysThe nasal cavity is one of the first barriers encountered by airborne ENMsThe proposed effort will lead to the development of a high contentmicrofluidic nasal air liquid interfaceALImodel to characterize expression of toxicity pathways in nasal epithelium after exposure to inhaled nanoparticlesSuccessful completion of this work can lead to the development of a new microfluidic nasal airway platform for nanotoxicology screening